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关键词： Cytomegalovirus   Congenital CMV   Viral latency   Neurons   CD4(+) T-cells   Hippocampus  

摘要： All human herpesviruses establish latency following the resolution of the primary infection. Among these, alpha-herpesviruses HSV-1, HSV-2 and VZV establish latency in neurons, whereas neurons are not traditionally considered a site of latency for other herpesviruses. Using a combination of in vivo murine models and ex vivo human fetal tissues, we discovered that cytomegalovirus (CMV), a ubiquitous beta-herpesvirus, can persist in neurons and that CD4(+) T-cell-derived interferon-gamma is critical in restricting active viral replication in this cell type. Furthermore, we show that mouse CMV can establish latency in neurons and that CD4(+) T-cells are essential in preventing viral reactivation. Our findings may have translational significance because human cytomegalovirus (HCMV) is the leading cause of congenital viral infections resulting in neurodevelopmental and neuroinflammatory lesions with long-term functional sequelae.

关键词： circadian rhythm disruption   Alzheimer's disease   neuroinflammation   hypoxia-inducible factor 3 alpha   bamboo leaf flavonoids  

摘要： Circadian rhythm disruption is a modifiable risk factor for Alzheimer's disease (AD) progression, marked by neuroinflammation, oxidative stress, and amyloid-beta (A beta) accumulation. Hypoxia-inducible factor 3 alpha (Hif3 alpha) has emerged as a key regulator of inflammatory and oxidative pathways. To evaluate the impacts of circadian disruption on AD progression and investigate the therapeutic potential of bamboo leaf flavonoids (BLFs), C57BL/6N mice (normal mice) and APP/PS1 transgenic mice (AD mice) were exposed to circadian disruption via randomized light exposure and stress, as the in vivo model. Then, BLFs were administered to assess effects on neuroinflammation, oxidative stress, and organ damage. Next, Nissl body staining and A beta protein immunohistochemistry were performed to evaluate the effects of BLFs on brain pathology. Through transcriptome sequencing, key factors and the related pathway were screened out. In vitro, molecular mechanisms were explored in PC12 cells treated with A beta 42 and Hif3 alpha siRNA fragments. Results demonstrated that circadian disruption increased oxidative stress and early liver and kidney damage degrees, with greater severity in AD mice. BLFs partially reversed oxidative damage and reduced A beta deposition. Transcriptome analysis revealed upregulation of Hif3 alpha in circadian-disrupted mice, linked to inflammation and oxidative stress. In vitro, the knockdown of Hif3 alpha reduced inflammation and normalized protein expression, which could be regulated by BLFs and suppressed AD progression. In conclusion, circadian disruption exacerbated AD progression via regulating Hif3 alpha/Rab7/TNF alpha/IL1 beta pathway. BLFs offered neuroprotection roles by mitigating inflammation and oxidative damage, highlighting Hif3 alpha as a promising target for AD therapy and biomarker development.

摘要： The adaptation of intestinal helminths to vertebrates evolved strategies to attenuate host tissue damage to support reproductive needs of parasites necessary to disseminate offspring to the environment. Helminths initiate the IL-25-mediated tuft cell-ILC2 circuit that enhances barrier protection of the host although viable parasites can target and limit the pathway. We used IL-25 to create small intestinal adaptation marked by anatomic, cell compositional and immunologic changes that persisted months after induction. Small intestinal adaptation was associated with heightened resistance to barrier pathogens, including in the lung, and sustained by transcriptionally and epigenetically modified, tissue-resident, memory-effector ILC2s distinct from those described by innate 'training'; epithelial stem cells remained unaltered. Despite requiring IL-25 for induction, memory ILC2s maintained an activated state in the absence of multiple alarmins and supported mucosal resilience while avoiding adverse sensitization to chronic inflammation, revealing a pathway for deploying innate immune cells to coordinate a distributed mucosal defense.

关键词： Crohn's disease   Mesenteric fat   Fibrogenesis   Group 1 Innate lymphoid cell  

摘要： Background Creeping fat is a characteristic of Crohn's disease and impacts the disease course. We evaluated creeping fat formation, focusing on innate lymphoid cell-mediated fibrogenesis and its clinical significance. Methods Patients with inflammatory lesions in the ileum (the most commonly affected area), who underwent surgical resection at Osaka University or Hyogo Medical University (n = 34), were included. The ileum and mesentery were obtained from three sites: the control, non-creeping fat part, and creeping fat part. The distribution and properties of the innate lymphoid cells were analyzed by cell isolation. Furthermore, the correlation between macrophages and their effects on adipose tissue and clinical course were also investigated in a prospective cohort study. Results Group 1 innate lymphoid cells in creeping fat were increased, correlating with inflammatory macrophages in the mesentery and showing higher interferon-gamma expression. Co-culture experiment involving stromal vascular fraction from the control mesentery and Group 1 innate lymphoid cells from creeping fat revealed increased mRNA expression of fibrosis-related genes and inflammatory markers of macrophages, although these changes were nullified by interferon-gamma-neutralizing antibody. Next, we examined the clinical importance of Group 1 innate lymphoid cells and identified their high frequency in creeping fat as a risk factor for early recurrence (P = 0.008, odds ratio: 1.19). Furthermore, the higher Group 1 innate lymphoid cell frequency group (>= 80%) had shorter relapse-free survival (P = 0.03). Conclusions Group 1 innate lymphoid cells and inflammatory macrophages contribute to creeping fat formation via interferon-gamma secretion, affecting post-surgery intestinal outcomes.

关键词： 糖尿病骨质疏松   网络药理学   分子对接   当归补血汤  

摘要： 目的：基于网络药理学，分子对接和动物实验，探究当归补血汤（DangGui BuXue Decoction， DGBXD）治疗糖尿病骨质疏松（Diabetic osteoporosis， DOP）的潜在靶点和作用机制。方法：通过网络药理学方法筛选/DGBX/T的活性化学成分，/检索当归补血汤与糖尿病/骨质疏松相关的靶点。构建药物-疾病靶点的蛋白质-蛋白质相互作用（PPI）网络。通过分子对接验证主要靶点与活性化学成分之间的相互作用。使用db/db糖尿病小鼠模型，通过ELISA，Western Blot和病理学等检测，验证DGBXD干预DOP的潜在靶点，并探究其作用机制。结果：网络药理学共获得黄芪作用的靶点共413个，当归作用的靶点共65个，检索出15330个基因作为DOP相关的疾病靶点。当归补血汤治疗DOP的靶点共202个，其中黄芪190个，当归11个。网络药理学富集分析表明DGBXD可能通过调节TNF-α表达和PI3K-AKT信号通路调节炎症因子表达，改善DOP的成骨异常。动物实验结果显示，与对照组相比，模型组小鼠的血清IL-6（P＜0.05），IL-8（P＜0.05）和TNF-α（P＜0.05）水平显著提高；DGBXD的干预可以抑制模型组过高的IL-6（P＜0.05），IL-8（P＜0.05）和TNF-α（P＜0.05）表达。病理结果显示DGBXD可以纠正异常炎症反应引起的骨形成紊乱。Western Blot结果进一步说明，与模型组相比，DGBXD的干预可以显著降低TNF-α（P＜0.05），AKT（P＜0.05），磷酸化AKT（P＜0.05）的蛋白表达，纠正BMP2的蛋白表达异常（P＜0.05）。结论：DGBXD可能通过调控TNF-α/PI3K-AKT/BMP信号通路，抑制炎症反应并增强BMP2的表达，从而促进骨基质的合成与矿化，缓解高糖诱导的成骨抑制，改善骨代谢平衡，达到对DOP的治疗作用。

关键词： 哺乳动物正呼肠孤病毒   多克隆抗体   间接ELISA  

摘要： 为了进行哺乳动物呼肠孤病毒（MRV）的多克隆抗体的制备以及间接ELISA检测方法的建立，本研究将MRV-3的μ1截短基因通过T4克隆至pET-32a（+）原核表达载体上，成功构建pET-32a-MRV-3-μ1质粒，通过BL21感受态细胞的转化，进行IPTG的诱导表达，成功表达出μ1截短蛋白，通过镍柱纯化的方法将纯化后的μ1蛋白用于昆明小鼠进行免疫，制备多克隆抗体，同时使用μ1蛋白进行抗原包被，建立间接ELISA方法。结果显示，重组μ1截短蛋白分子量为58 kDa，以包涵体的形式表达，同时制备的多克隆抗体可以使用Western blot实验和IFA特异的识别MRV-3表达的μ1蛋白。建立检测牛MRV-3血清的间接ELISA方法的变异系数小于10%；可以特异性识别牛MRV-3阳性血清，不识别牛流行性腹泻病毒、牛匈爱病毒和牛肠道病毒，为MRV-3临床检测奠定了基础。

关键词： non-Faradaic biosensor   impedimetric parameters   interleukin-8   disability  

摘要： Interleukin-8 (IL-8) is a critical biomarker associated with inflammation and disability in both adults and newborns. Conventional detection methods are often labor-intensive, time-consuming, and require highly trained personnel. Non-Faradaic impedimetric biosensors offer a label-free, rapid, and direct approach for IL-8 detection. While previous studies have primarily focused on capacitance and phase changes, the potential of other impedimetric parameters remains underexplored. In this study, a gold interdigitated electrode (Au-IDE)-based non-Faradaic biosensor was developed for IL-8 detection, evaluating multiple impedimetric parameters, including capacitance, impedance magnitude (Zmod), real impedance (Zreal), and imaginary impedance (Zimag). Among these, Zimag exhibited the lowest limit of detection (LoD) at 90 pg/mL, followed by Zmod at 120 pg/mL, and capacitance at 140 pg/mL, all significantly below the clinical threshold of 600 pg/mL. In contrast, Zreal displayed the highest LoD at 1.3 ng/mL. Sensitivity analysis revealed that Zimag provided the highest sensitivity at 13.1 k Omega/log (ng/mL), making it the most effective parameter for detecting IL-8 at low concentrations. The sensitivity of Zmod and Zreal was lower, while capacitance sensitivity was measured at 20 nF/log (ng/mL). These findings highlight the importance of investigating alternative impedimetric parameters beyond capacitance to optimize biosensor performance for biomarker detection. This study demonstrates that non-Faradaic biosensors, despite their capacitive-based nature, can achieve enhanced sensitivity and detection limits by leveraging additional impedimetric parameters, offering a promising approach for rapid and effective IL-8 detection.

关键词： IL-17   IL-23   Biologics   Plaque psoriasis   Metabolic syndrome   Metabolic indicators  

摘要： This study aims to compare the efficacy of IL-17 and IL-23 biologics in the treatment of plaque psoriasis (Psoriasis vulgaris) in patients with metabolic syndrome (MetS) and to explore the effects of different biologics on metabolic indicators, particularly regarding the differences in efficacy during long-term treatment. This is a randomized controlled clinical trial involving 120 moderates to severe plaque psoriasis patients, of which 60 have metabolic syndrome and 60 do not. The patients were randomly assigned to three groups: IL-17 biologics group, IL-23 biologics group, and cyclosporine control group. Treatment lasted for three months, with evaluation indicators including psoriatic lesion assessment (PASI score), blood glucose levels, lipid profile (triglycerides, HDL-C), inflammatory markers (CRP, ESR, IL-6), etc. Patients were assessed at baseline, after one month, and after three months of treatment for both clinical efficacy and changes in metabolic indicators. Both IL-17 and IL-23 biologics demonstrated superior efficacy compared to cyclosporine in treating plaque psoriasis. After one month and three months of treatment, PASI scores in the IL-17 and IL-23 groups were significantly lower than in the control group, and the therapeutic effects were more pronounced (P < 0.05). The IL-17 and IL-23 groups also showed better improvements in blood glucose, blood lipids (TG and HDL-C), and inflammatory markers (CRP, ESR, IL-6) compared to the control group. After three months of treatment, fasting blood glucose, fasting insulin, triglycerides, and CRP levels were significantly lower in the IL-17 and IL-23 groups than in the control group (P < 0.05). Metabolic syndrome had some impact on treatment outcomes, with the efficacy of IL-17 and IL-23 biologics being lower in patients with metabolic abnormalities compared to those without metabolic syndrome. However, the IL-23 biologic showed less impact from metabolic syndrome. IL-17 biologics had a rapid effect in the sho

摘要： Infection with Mycobacterium tuberculosis (Mtb) can produce a wide spectrum of clinical manifestations, ranging from active tuberculosis (TB) to asymptomatic latent infection. Although CD4 T-cells are key immune effectors to control TB, early after infection, the innate immune response must play a role in tackling the disease. Here, we performed in-depth analyses of the acute immune response to MTBVAC, a candidate vaccine engineered from Mtb with the aim of protecting adults from pulmonary TB disease, still a major global challenge. scRNA-seq shows expansion of CD4+ and cytotoxic gamma delta T-cells, data confirmed by flow cytometry. CD4 T-cells exhibited lower HLA-DR and higher L-selectin expression, compared to BCG-stimulation, indicating differential activation or dynamics. Importantly, MTBVAC-activated gamma delta T-cells had a unique cytotoxic CD16+GZMB+ phenotype, reminiscent of effector cells found in Mtb positive individuals controlling infection. IFN-gamma and TNF-alpha were released in cultures, while IL-17A/F were almost undetectable.

关键词： tuberculosis   interleukin-12   immunotherapy   molecular mechanisms  

摘要： Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global health challenge, affecting millions annually and leading to substantial mortality, particularly in developing countries. The pathogen's ability to persist latently and evade host immunity, combined with the emergence of drug-resistant strains, underscores the need for innovative therapeutic strategies. This review highlights the crucial role of interleukin-12 (IL-12) in coordinating immune responses against TB, focusing on its potential as an immunotherapy target. IL-12, a key Th1 cytokine, enhances cellular immunity by promoting Th1 cell differentiation and IFN-gamma production, vital for Mtb clearance. By stimulating cytotoxic T lymphocytes and establishing immune memory, IL-12 supports robust host defense mechanisms. However, the complexity of IL-12 biology, including its roles in pro-inflammatory and regulatory pathways, necessitates a nuanced understanding for effective therapeutic use. Recent studies have shown how IL-12 impacts T cell synapse formation, exosome-mediated bystander activation, and interactions with other cytokines in shaping T cell memory. Genetic defects in the IL-12/IFN-gamma axis link to susceptibility to mycobacterial diseases, highlighting its importance in TB immunity. The review also addresses challenges like cytokine imbalances seen in TNF-alpha/IFN-gamma synergy, which exacerbate inflammation, and the implications for IL-12-based interventions. Research into modulating IL-12, including its use as an adjuvant and in recombinant vaccines, promises improved TB treatment outcomes and vaccine efficacy. The review concludes by stressing the need for continued investigation into IL-12's molecular mechanisms towards precision immunotherapies to combat TB and its complications.